Studies in infectious disease and autoimmunity models have shown that immune responses to both self and foreign antigens are frequently dominated by induction of a particular Th1/Th2 subset with profound consequences for clinical outcome. Although the inflammatory effector function of Th1 cells is essential for the clearance of intracellular pathogens, it is also responsible for the tissue damage typical of organ-specific autoimmunity. Th2 cells which play an important role in the clearance of many helminthic infections function as suppressor cells or ineffectual bystanders in organ-specific autoimmune diseases. We have focused our studies on the role of IL-12 and its receptor in susceptibility both to organ-specific autoimmunity and to chronic infection by intracellular parasites and on the role of IL-18 and its receptor in the potentiation of Th1 differentiation. Collagen-induced arthritis (CIA) is an animal model of inflammatory polyarthritis that is induced is induced in susceptible strains of rats and mice by intradermal immunization with heterologous type II collagen. We have used a panel of both susceptible and resistant strains of mice in which either IFN-g or IL-10 signaling has been abolished by gene deletion. Disruption of the gene for either IFN-g or its receptor renders resistant mice highly susceptible and this susceptibility is dependent on the presence of IL-12. More surprisingly, neutralization of IL-4 either by disruption of the gene in the animal or by administration of a neutralizing antibody also reduced the onset and severity of arthritis. Although these studies provide valuable insights into the role of individual cytokines in the pathogenesis of organ-specific autoimmune diseases, the translation of these findings to the treatment of autoimmune diseases in man is problematic. These studies demonstrate that the prototypic Th1 cytokine, IFN-g, can exert a protective effect early in the induction phase of disease, particularly in resistant strains of mice. Although our results clearly demonstrate that IL-12 is required for disease induction, other studies have shown that treatment of established arthritis with anti-IL-12 potentiates disease, while treatment with IL-12 suppresses disease. Similarly, while we have shown that IL-4 is required for development of arthritis, other groups have shown that prolonged treatment of mice with anti-IL-4 exacerbates disease. During the course of our studies on the role of IL-12 in susceptibility to CIA, we noted that one subline of B10.Q mice, B10.Q/J, that are normally susceptible to disease induction, was completely resistant. Further studies demonstrated that this strain has a global defect in the generation of Th1 responses and antigen-specific T cells derived from this strain failed to produce IFN-g. T cells from this strain could produce normal amounts of IFN-g when activated by IL-12/IL-18 independent stimuli, suggesting that the defect appeared to be a failure to respond to IL-12. In addition to T cells, NK cells from this strain failed to produce IFN-g when stimulated with IL-12. The capacity of NK cells, but not T cells, to produce IFN-g in response to IL-12 could be partially restored by the addition of IL-18. The expression of the IL-12R on cells of the B10.Q/J strain was normal; however, activated T cells failed to signal normally through the IL-12R and manifested a defect in the phosphorylation of Stat4. This defect could be overcome by high concentration of IL-12 or by prolonged incubation times. As Stat4 itself is normal in this strain, the defect in IL-12R signaling appears to be localized between the IL-12R complex and Stat4. We further characterized the defect in IL-12 responsiveness in this strain, in the context of the in vivo immune response to T. gondii infection. Our results demonstrate that B10.Q/J mice are highly susceptible to parasite challenge. This stems from a selective defect in IFN-g production during the first 4-5 days of infection. The genetic element controlling defective early IL-12 dependent lymphokine response is inherited as a recessive, autosomal fashion and is distinct from Stat4. The effects of this mutation on the IFN-g response can be corrected by IL-18 administration. Patients with atypical mycobacterial infections and Salmonella infections have also been shown to manifest mutations in the IL-12 signalling pathway. The B10.Q/J mouse should prove to be a valuable resource and model for the analysis of complex defects in the IL-12 signaling pathway. We have demonstrated that the primary effect of IL-18 on Th1 differentiation is mediated by its capacity to directly upregulate IL-12 receptor expression resulting in enhanced IL-12 mediated signaling. The enhancement of IL-12 receptor expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development. Although the major function of IL-18 is to enhance Th1 differentiation, IL-18 can also induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanism regulates these diammetrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor alpha-chain expression. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18R expression was observed. IL-12 mediated upregulation of IL-18R expression required interferon-gamma (IFN-g). In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18R expression. Thus, positive negative regulation of the IL-18R by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.